POMC AMPKα1 deletion drives male-specific BAT thermogenesis and obesity resistance

Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) play a critical role in energy homeostasis. 5’-adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase, which acts as the main energy sensor in the cell. The heterotrimeric AMPK results from the combination of a catalytic α subunit (α1, α2) with two regulatory subunits, β (β1, β2) and γ (γ1, γ2 and γ3). Hypothalamic AMPK plays a key role in the control of energy balance, but current evidence shows that the precise combination of its heterotrimeric components determines its physiological action. Our findings show that AMPKα1 ablation in POMC neurons has a sex-dependent protective effect against diet-induced obesity because of increased thermogenesis in brown adipose tissue (BAT) in males, but not in females. At the molecular level, deletion of AMPKα1 in POMC neurons disrupts the ARC phosphoproteome and is associated with ameliorated endoplasmic reticulum (ER) stress and reduced ceramide content. These findings highlight the complex function of the different AMPK subunits in the hypothalamic regulation of energy balance.